It has become evident that humoral responses play crucial roles in the protective immunity against infection by HIV-1, and in preventing its progression to disease states. It has been demonstrated that higher endogenous neutralizing antibody titers correlate with better clinical conditions, and low or decreasing neutralizing antibody titers with disease progression. Wendler I., V. Bienzle, and G. Hunsman, AIDS Res. Human Retroviruses 3:157-163 (1987). It has also been demonstrated that ARC and AIDS patients treated with hyperimmune plasma from asymptomatic HIV-1 seropositive individuals showed clinical improvement, which correlated with reduction in HIV-1 viraemia. Jackson C. G., et al., Lancet 2:647-651 (1988); Karpas A., et al., Proc. Natl. Acad. Sci. USA 87:7613-7617 (1990); Karpas A., et al., Proc. Natl. Acad. Sci. USA 85:9234-9237 (1988). More recently, some preliminary studies showed that chimpanzees injected with a mouse-human chimeric HIV-1 neutralizing monoclonal antibody (MAb) were protected from infection by the virus. Emini E. A. et al. vol. 2, p. 72. Th. A. 64. Abstr. VII International Conference on AIDS (1991). In short, monoclonal antibodies which neutralize HIV-1 infection are likely to be useful in post-exposure prophylaxis and in therapy.
The envelope proteins of HIV-1, gp120 and gp41, are known to be the major targets for the HIV-1 neutralizing activity in the sera of HIV-1-infected individuals, and of animals immunized with the viral proteins. Several neutralization sites have been identified in gp120, including an immunodominant epitope in the V3 region (amino acid residues: 308-322), commonly known as the principal neutralization determinant (PND). See International Application No. PCT/US88/01797. Antibodies raised against this continuous epitope usually exhibit neutralizing activity.
Anti-PND antibodies do not block virus binding to CD4 on T cells, but prevent virus internalization by the T cells subsequent to CD4 binding. Skinner M. A., et al. J. Virol. 62:4195-4200 (1988). Another continuous neutralization site on gp120 is located in the CD4 region (amino acid residues: 413-447), which is involved in CD4-gp120 interaction. International Patent Application No. PCT/US90/02261. Antibodies to this region exhibit broad neutralizing activity against divergent HIV-1 isolates, but this neutralization site appears to be rather immunosilent in HIV-1 infected individuals. Sun N. C., et al., J. Virol. 63:3579-3585 (1989).
Sera from most HIV-1 infected individuals usually have low levels of broadly HIV-1 neutralizing antibodies, and such neutralizing antibodies as are present are usually directed to conformational or discontinuous epitopes on gp120. For example, a human MAb, designated I5e, which recognizes a discontinuous epitope on gp120, has been shown to be involved in CD4 binding and in antibody neutralization of multiple HIV-1 isolates. Ho D. D., et al., J. Virol, 65:489-493 (1991). Another HIV-1 neutralizing murine MAb, designated G3-4, which identified another distinct conformational epitope on gp120, is involved in the interaction with CD4. U.S. application Ser. No. 07/692,099 (pending).
Some other MAbs which neutralize HIV-1 are described below.